thiostrepton and Carcinoma--Ovarian-Epithelial

Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo.. Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative real-time polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets.. Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1, CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo.. Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Ascites; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Drug Synergism; Female; Forkhead Box Protein M1; Humans; Molecular Targeted Therapy; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Platinum; RNA, Messenger; Thiostrepton

Aberrantly activated FOXM1 (forkhead box protein M1) leading to uncontrolled cell proliferation and dysregulation of FOXM1 transcription network occurs in 84% of ovarian cancer cases. It was demonstrated that thiostrepton, a thiazole antibiotic, decreases FOXM1 expression. We aimed to determine if targeting the FOXM1 pathway with thiostrepton could improve the efficacy of paclitaxel and cisplatin in human ovarian cancer ascites cells ex vivo.. Human ovarian cancer cell lines and patients' ascites cells were treated with paclitaxel, cisplatin, and thiostrepton or a combination for 48 hours, and cytotoxicity was assessed. Drug combination effects were determined by calculating the combination index values using the Chou and Talalay method. Quantitative reverse transcriptase-polymerase chain reaction was performed to determine changes in FOXM1 expression and its downstream targets.. Ovarian cancer cell lines and the patients' ascites cancer cells had an overexpression of FOXM1 expression levels. Targeting FOXM1 with thiostrepton decreased FOXM1 mRNA expression and its downstream targets such as CCNB1 and CDC25B, leading to cell death in both cell lines and patients' ascites cancer cells. Furthermore, addition of thiostrepton to paclitaxel and cisplatin showed synergistic effects in chemoresistant ovarian cancer patients' ascites cells ex vivo.. Targeting FOXM1 may lead to novel therapeutics for chemoresistant epithelial ovarian cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Ascites; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Drug Synergism; Female; Forkhead Box Protein M1; Humans; Molecular Targeted Therapy; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Signal Transduction; Thiostrepton

Chemoresistance to anti-cancer drugs substantially reduces survival in epithelial ovarian cancer. In this study, we showed that chemoresistance to cisplatin and paclitaxel induced the epithelial-mesenchymal transition (EMT) and a stem cell phenotype in ovarian cancer cells. Chemoresistance was associated with the downregulation of epithelial markers and the upregulation of mesenchymal markers, EMT-related transcription factors, and cancer stem cell markers, which enhanced invasion and sphere formation ability. Overexpression of FOXM1 increased cisplatin-resistance and sphere formation in cisplatin-sensitive and low FOXM1-expressing ovarian cancer cells. Conversely, depletion of FOXM1 via RNA interference reduced cisplatin resistance and sphere formation in cisplatin-resistant and high FOXM1-expressing cells. Overexpression of FOXM1 also increased the expression, nuclear accumulation, and activity of β-CATENIN in chemoresistant cells, whereas downregulation of FOXM1 suppressed these events. The combination of cisplatin and the FOXM1 inhibitor thiostrepton inhibited the expression of stem cell markers in chemoresistant cells and subcutaneous ovarian tumor growth in mouse xenografts. In an analysis of 106 ovarian cancer patients, high FOXM1 levels in tumors were associated with cancer progression and short progression-free intervals. Collectively, our findings highlight the importance of FOXM1 in chemoresistance and suggest that FOXM1 inhibitors may be useful for treatment of ovarian cancer.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Blotting, Western; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Cell Proliferation; Cisplatin; Disease Progression; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; Female; Forkhead Box Protein M1; Forkhead Transcription Factors; Humans; Immunohistochemistry; Mice, Inbred NOD; Mice, SCID; Neoplasms, Glandular and Epithelial; Neoplastic Stem Cells; Ovarian Neoplasms; Paclitaxel; RNA Interference; Survival Analysis; Thiostrepton; Tumor Burden; Xenograft Model Antitumor Assays